This project has attempted to apply our understanding of the cellular mechanisms involved in in vitro anti-MHC responses to in vivo transplantation responses. In studying skin allograft rejection, we have identified the phenotype, specificity, and interaction capabilities of the T cells able to initiate and effect in vivo rejection responses. We found that in vivo exposure of effector cells to skin allografts under conditions in which T-helper cells were not activated resulted in the inactivation of the effector cells and longterm retention of the skin allograft. We found that rejection across a class I MHC barrier could occur in mice depleted of CD8+ T cells by in vivo administration of anti-CD8 mAb, but that the in vivo effector cells were a novel population of anti-CD8 resistant CD8+ T cells that had down-modulated their CD8 surface expression and were highly resistant to anti-CD8 blockade of their cytolytic function. In addition, we have demonstrated that rejection of skin allografts across a class II MHC barrier requires the production of endogenous IFNgamma, presumably to induce class II expression on all the cells of the graft and make them recognizable by class II allospecific effector cells. Finally, we have assessed the cellular mechanisms mediating the rejection of fetal pancreas and Islet cell allografts.